Amyloid β (Aβ) 1-42 peptide is believed to be one of the key factors in development and progression of Alzheimer's disease. While the exact pathogenic role of amyloid β-peptide in Alzheimer's disease has not yet been definitely established, accumulating evidence supports the hypothesis that amyloid β-peptide production and deposition in the brain is a causative event in Alzheimer's disease. Therefore, the problem of production, accumulation, and clearance of amyloid β-peptide in the brain has emerged as one of the possible rational approaches for the treatment of Alzheimer's disease.
It has been recently found that intravenous IgG preparations contain antibodies specific to Aβ 1-42 amyloid peptide. Also, in two small human trials, intravenous IgG was found to slow down the progression of Alzheimer's disease (Dodel, R., et al., “Intravenous Immunoglobulins containing antibodies against b-amyloid for the treatment of Alzheimer's disease,” J. Neurol. Neurosurg. Psychiatry, 75:1472-1474 (2004); and Dodel, R., et al., “Human antibodies against amyloid beta peptide: A potential treatment for Alzheimer's disease,” Ann. Neurol, 52:253-256 (2002)). Although the mechanism of action of IgG in this indication remains to be elucidated, the authors speculated that the simple systemic removal of the offensive Aβ 1-42 peptide might be the reason for the efficacy of intravenous IgG.
Immunoglobulin M (IgM) is the immunoglobulin found in third largest concentration in the serum of most animals (about 6-10% of total immunoglobulin pool). Normal plasma concentrations of IgM in humans are from about 0.6 to about 2.5 mg/ml for males and from about 0.7 to about 2.8 mg/ml for females.
IgM is a 19S molecule with a molecular weight of 950 kDa and is made up of five identical 180 kDa subunits. Each of these subunits is similar in structure to the monomer of IgG, except they possess four, rather than three, CH domains. The IgM monomers are linked by disulfide bonds in a circular fashion to form a star, and a small cysteine-rich polypeptide called the J-chain (20 kDa) links two of the units (see FIG. 1). IgM molecules are secreted intact by plasma cells, and the J-chain must therefore be considered to be an integral part of this molecule. The plasma half-life of IgM is about 5.1 days.
IgM is the major immunoglobulin isotype produced in a primary immune response. It is also produced in a secondary response, but this tends to be masked by the predominance of IgG. Although produced in a relatively small quantity, IgM, due to its pentameric structure, is considerably more efficient (on a molar basis) than IgG at complement activation, opsonization, neutralization of viruses, and agglutination. Most of the isoagglutinins in human serum, which recognize blood type antigens A and B, are of the IgM class. Therefore, some special measures may be utilized during purification to remove isoagglutinins and make the preparation more compatible with A and B blood types.
Passive immunization using IgM-containing immunoglobulin preparations can provide advantages in the treatment and/or prevention of disorders or diseases associated with amyloid peptides.